PSGL-1 is a glycoprotein on leukocytes that plays a critical role in cell adhesion, functioning as a possible counter receptor to P-selectin, E- selectin and L-selectin. Although this adhesion molecule likely plays a major role in inflammation, thrombosis, and atherosclerosis through the accumulation of leukocytes during host defense, there is little direct evidence for the true physiologic role of this protein. We have prepared a PSGL-l deficient mouse by gene targeting technology. Through a breeding program, we are also establishing colonies of PSGL-1/P- selectin deficient, PSGL-1/E-selectin deficient, and PSGL-1/L-selectin deficient mice. The primary goal of this project is to determine the significance of PSGL-1 delivering leukocytes to the appropriate anatomic site in a variety of pathologic processes studied in physiologically and pathologically relevant animal models. Given the importance of graft versus host disease following bone marrow transplant in humans, we will evaluate the role of PSGL-1 in GVH disease using a mouse model. A PSGL-1 deficient transplant recipient mouse and a PSGL-1 deficient transplant donor mouse will be prepared by cross-breeding, and allogeneic bone marrow transplantation will be performed with these mice. GVH disease will be measured and mouse survival post-transplant will be determined in recipients when donors, recipients, both or neither are deficient in PSGL-1. The role of PSGL-1 in thrombosis will be evaluated using novel mouse models, including a model of warfarin-induced skin necrosis in a heterozygous protein C deficient mouse.